10.00-10.20 อ.ปรมัตถ์ (Symsanofi)Epidemiology and diagnosis vascular calcification in CKD

Epidemiology and diagnosis vascular calcification in CKD Paramat Thimachai,MD Division of Nephrology, Department of Medicine Phramongkutklao Hospital and College of Medicine

Outline • Epidemiology • Pathophysiology • Diagnosis vascular calcification in CKD 2

Introduction A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: 1. Abnormalities of calcium, phosphorus, PTH or vitamin D metabolism 2. Abnormalities of bone turnover, mineralization, volume, linear growth or strength 3. Vascular or other soft tissue calcification KDIGO. Kidney Int. 2009; 76 (suppl 113):S1-S130. 3 Isakova T, el al. Kidney Int. 2011;79:1370–1378.

Cause of death in CKD 4 Nelson AJ, et al. J Am Coll Cardiol Basic Trans Science 2020;5:398–412 .

CKD-MBD and Cardiovascular disease 5 Indian Heart J. 2017 Mar-Apr;69(2):255-265. Joachim Jankowski et al. Circulation. 2021;143:1157–1172

Cardiovascular disease burden in CKD 6 Nelson AJ, et al. J Am Coll Cardiol Basic Trans Science 2020;5:398–412 .

Vascular calcifications: Calciphylaxis Calciphylaxis is associated with high morbidity and mortality despite treatment, mainly from sepsis. Risk factors • High calcium-phosphate product • Elevated parathyroid hormone • Hypoalbuminaemia • Diabetes • Obesity • Warfarin use • Female sex • Protein C or S deficiency 7 Olaoye OA, Koratala A. BMJ Case Rep 2017.

Epidemiology Vascular calcification prevalence increases as kidney function decline Computed tomography At start of After 3 years 100% dialysis on dialysis Patients with CAC (%) 83%*** 80% CKD 3/4 57%** ~57 yrs. GFR 33 ml/min 60% Normal ~58 yrs. 40% 40%* GFR 99 ml/min 52 yrs. 20% 13%* 47 yrs. 0% Russo Russo RIND TTG *Russo et al. Am J Kidney Dis. 2004; 44:1024-30 **Spiegel Hemod Internat. 2004; 8:265 8 *** Chertow Kidney Int. 2002; 62:245-52

Vascular calcification in CKD Atherosclerosis Medial calcification (Monckeberg’s sclerosis) • Usually asymptomatic pseudohypertension • Intimal calcification • Inflammatory associated with: • Lipid deposition • Disturbances of Ca, P and vitamin D • Ischemia-related, occlusion metabolism (ESRD) • LVH from increased left ventricular overload 9 • Rhythm disturbances

Calcified Arteries Determines CV Death in CKD Maximillian Rogers, et al. J Am Heart Assoc. 2013;2:e000481 10

Vascular calcification in CKD-MBD Catherine M. Shanahan Nat Rev Nephrol. 2013 Nov;9(11):661-70. 11 Elijah Kakani et al. Seminars in Dialysis. 2019;00:1–9.

Vascular calcification in CKD-MBD Chen NX. J Am Soc Nephrol. 2008;19:213–216. 12 M, et al. Calcif Tissue Int. 2013;93:365–373.

Vascular calcification in CKD-MBD 13 Andrea Tóth, et al. Antioxidants 2020, 9(10), 963

Vascular calcification in CKD Patient ↑Ca, ↑phosphate, ↑iPTH, ↓klotho, ↑inflammation, ↑cellular senescence Arterial Valve Myocardial calcification calcification calcification Plaque Arterial vulnerability stiffness LVH Sudden cardiac death Atherosclerotic Heart failure Stroke events Nelson AJ, et al. J Am Coll Cardiol Basic Trans Science 2020;5:398–412 . 14

Diagnostic Tests 15 Edward R. Smith, et al. Adv Chronic Kidney Dis. 2019;26(6):445-463

Diagnostic Tests 16 Edward R. Smith, et alAdv Chronic Kidney Dis. 2019;26(6):445-463

Diagnostic Tests 17 Edward R. Smith, et alAdv Chronic Kidney Dis. 2019;26(6):445-463

Vascular calcification in CKD The reference standard in the detection of cardiovascular calcifications in CKD and in the general population is the CT-based CAC score, but other may yield comparable information, more easily available techniques • lateral abdominal X-ray • echocardiography (valvular calcification) • pulse wave velocity (PWV) measurements 1N8elson AJ, et al. J Am Coll Cardiol Basic Trans Science 2020;5:398–412 .

Diagnosis of CKD-MBD: vascular calcification KDIGO CKD-MBD 2009 KDIGO CKD-MBD 2017 3.3.1. In patients with CKD stages 3–5D, we suggest 3.3.1: In patients with CKD G3a–G5D, we suggest that a lateral abdominal radiograph can be used to that a lateral abdominal radiograph can be used detect the presence or absence of vascular to detect the presence or absence of vascular calcification, and an echocardiogram can be used calcification, and an echocardiogram can be to detect the presence or absence of valvular used to detect the presence or absence of calcification, as reasonable alternatives to valvular calcification, as reasonable alternatives computed tomography-based imaging (2C). to computed tomography-based imaging (2C). 3.3.2. We suggest that patients with CKD stages 3– 3.3.2: We suggest that patients with CKD G3a– 5D with known vascular/valvular calcification be G5D with known vascular or valvular calcification considered at highest cardiovascular risk (2A). It is be considered at highest cardiovascular risk (2A). reasonable to use this information to guide the It is reasonable to use this information to guide management of CKD–MBD (not graded). the management of CKD-MBD (Not Graded). Kidney International (2009) 76 (Suppl 113), S3–S8 Kidney International Supplements (2017) 7, 1–5 19

Vascular calcification in CKD • Electron beam CT (EBCT) or multisided CT (MSCT) remain the gold standard. • Pulse wave velocity (PWV) and abdominal aortic calcifications seemed to be reasonably good predictors of CAC scores, whereas the value of IMT, valvular calcification, and especially pulse pressure was limited. • plain X-ray and echocardiography were reasonable alternatives to the gold standard of CT-based imagine. 20 Kidney International (2009) 76 (Suppl 113), S3–S8

Coronary arterial calcification, CAC • Mayo Clinic EBCT Guidelines Radiology 129:7-10, October 1978 Clin Radiol. 2019 Dec;74(12):973.e7-973.e14. Markuszewski, et al. Cardiology Journal 13 (2006): 459-464. 21

Coronary arterial calcification, CAC CKD not on dialysis CKD on dialysis Survival probability Patients with the most severe calcification had a mortality rate 4 times that of patients without calcification • Survival was significantly worse in patients with a higher baseline CAC score (P<0.0017) • Presence and severity of CAC at initiation of hemodialysis is an important predictor of long- • Progression of CAC score was an term survival independent predictive factor of cardiac Block et al, Kidney Int, 2007 events Russo et al, Kidney Int, 2011 22

PLAIN film X-RAY Site; • Lateral abdominal x-ray : Abdominal aortic calcification • Pelvic x-ray : iliac and femoral artery calcification • Hands x-ray : digital and radial artery (A) (angiogram-like; B and C ). (D) Intima calcification, Medial calcification :media calcification, Intima and media present as discrete plaques present as uniform linear railroad track- calcification is reflected with irregular and patchy type as discordances distribution 23 London GM, et al. Nephrol Dial Transplant 2003;18: 1731–1740

Kauppila score • Abdominal Aortic Calcification Score Lumbar aortic calcification can be graded and composite summary scores are reproducible. This technique appears to provide a simple, low cost assessment of subclinical vascular disease. 24 Kauppila LI, et al. Atherosclerosis. 1997 Jul 25;132(2):245-50.

Arterial calcification and cardiovascular risk in CKD 5D patients Prospective study in 110 HD patientsProbability of survival [%]Calcification Score: 100 0 1 75 2 50 3 25 4 0 0 20 40 60 80 Follow-up (Months) 25 Blacher J et al., Hypertension 2001; 38:938

Impact-CKD study group THE IMPACT OF PREVALENCE OF ABDOMINAL AORTA CALCIFICATION OF THAI CHRONIC KIDNEY DISEASE STUDY • Multicenter, cross-sectional study primarily aimed to determine prevalence of abdominal aortic calcification (AAC) detected by plain lateral abdominal radiograph • Patients (N = 1500), aged 18-70 years, with CKD stages 3-5D for ≥3 months prior to evaluation, were enrolled at 24 study centers in Thailand; 54.3% were non-dialysis patients. 26 Lumlertgul D, et al. Ther Apher Dial. 2017 Dec;21(6):611-619.

Kauppila score • Abdominal Aortic Calcification Score Lumbar aortic calcification can be graded and composite summary scores are reproducible. This technique appears to provide a simple, low cost assessment of subclinical vascular disease. 27 Kauppila LI, et al. Atherosclerosis. 1997 Jul 25;132(2):245-50.

Impact-CKD study group * Prevalence as of AAC ≥ 1 N = 1500 AAC =0: 439 AAC ≥ 1: 1061 (70.7%) (29.3%) N = 1500 Mean (SD): 3.7 (4.3) Median (P25-75): 2.0 (0.0-6.0) Min-max: 0-22 Prevalence* of AAC in Thai CKD patients was 70.7% with a 95% CI: 68.4% to 73.0% 28 Lumlertgul D, et al. Ther Apher Dial. 2017 Dec;21(6):611-619.

Impact-CKD study group The AAC cut-off AAC score of ≥ 5 was justified as cut-off AAC 1-4: AAC: 0-4 599 (39.9%) CORD Study, Verbeke F et al. 2011. Clin J Am Soc Nephrol 6: 153-159 A cohort of 2 year follow-up on mortality outcome of 1084 patients on dialysis with different Kauppila AAC scores. AAC ≥ 5: 462 (30.8%) 29 Lumlertgul D, et al. Ther Apher Dial. 2017 Dec;21(6):611-619.

Impact-CKD study group Severe AAC (as of score ≥ 5) Percent P = 0.0001 P = 0.0009 P = 0.0474 P = 0.0116 N = 278 289 Not on 254 dialysis 247 686 N = 814 432 P-value: Fisher’s exact test Lumlertgul D, et al. Ther Apher Dial. 2017 Dec;21(6):611-619. 30

Vascular calcification in CKD 31 Nelson AJ, et al. J Am Coll Cardiol Basic Trans Science 2020;5:398–412 .

Adragão score • The Adragão score quantifies calcification of 32 the iliac, femoral, radial, and digital arteries observed on plain radiographs of the hands and pelvis. • The final value ranges between 0 and 8 points (0 to 4 in the pelvis and 0 to 4 in the hands). • In one study, a vascular calcification score ≥3 had an almost fourfold higher risk of cardiovascular mortality Adragao T, et al. Nephrol Dial Transplant. 2004;19(6):1480. Epub 2004 Mar 19. JordiBover, et al. Nefrologia. 2016;3 6(6):587–59

Alternative studies Echocardiography Pulse wave velocity (PWV) • Assessment of ventricular structure • Increase PWV associate with and function, and cardiac valves calcification score Mitral valve calcification • Good predictors of CAC scores • Increase aortic PWV predict -10-40% in patients on dialysis cardiovascular death and all- Aortic valve calcification cause mortality -25-55% in patients on dialysis • Associated with an adverse cardiovascular outcome and high mortality in patients on dialysis 33 Thomas H. Marwick, et al. Kidney International (2019) 96, 836–849 Haydar AA, et al. Kidney Int 2004; 65: 1790–1794. Stompor T, et al. Int J Artif Organs 2006; 29: 736–744. Raggi P, et al. Kidney Int 2007; 71: 802–807.

Identification of Novel Biomarkers 34 Kidney360 February 2021, 2 (2) 279-289

Take home message • Cardiovascular calcification is part of CKD-MBD. • Vascular calcification and its progression are independent predictors of hospitalization, cardiovascular events, and morbidity and mortality, in CKD patients even before starting dialysis. • The 2009 KDIGO (and 2015 controversies) guidelines consider using information on vascular calcification reasonable for guiding the management of CKD-MBD. • Vascular calcification progression is potentially modifiable. 35